Polymeric endoluminal paving process

ABSTRACT

A method for applying a paving material to a tissue surface is described. The method involves positioning a non-fluent polymeric material at the surface to be paved, rendering the material fluent, contacting the fluent polymer with the tissue surface, and allowing the polymer to return to its non-fluent condition.

This application is a file wrapper continuation of application Ser. No.08/118,978, filed Sep. 9, 1993, now abandoned which is acontinuation-in-part of Ser. No. 07/987,357, filed Dec. 7, 1992, nowabandoned, which is a continuation of Ser. No. 07/857,700, filed Mar.25, 1992, issued as U.S. Pat. No. 5,213,580, which is a file wrappercontinuation of Ser. No. 07/593,302, filed Oct. 3, 1990, now abandoned,which is a file wrapper continuation of Ser. No. 07/235,998, filed Aug.24, 1988, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a novel method for the in vivo paving of theinterior of organs or organ components and other tissue cavities, and toapparatus and polymeric products for use in this method. The tissuesinvolved may be those organs or structures having hollow or tubulargeometry, for example blood vessels such as arteries or veins, in whichcase the polymeric products are deposited within the naturally occurringlumen. Alternatively, the tissue may be a normally solid organ in whicha cavity has been created either as a result of a surgical procedure, apercutaneous intervention, an accidental trauma, or disease.

The hollow or tubular geometry of organs commonly has functionalsignificance such as in the facilitation of fluid or gas transport(blood, urine, lymph, oxygen or respiratory gasses) or cellularcontainment (ova, sperm). Disease processes may affect organ tissue orits components by encroaching upon, obstructing or otherwise reducingthe cross-sectional area of the hollow or tubular elements.Additionally, other disease processes may violate the native boundariesof the hollow organ and thereby affect its barrier function and/orcontainment ability. The ability of the organ or structure to properlyfunction can then be severely compromised. A good example of thisphenomena can be seen in the coronary arteries.

Coronary arteries, or arteries of the heart, perfuse the cardiac musclewith arterial blood. They also provide essential nutrients, removal ofmetabolic wastes, and gas exchange. These arteries are subject torelentless service demands for continuous blood flow throughout the lifeof the patient.

Despite their critical life supporting function, coronary arteries areoften subject to attack through several disease processes, the mostnotable being atherosclerosis (hardening of the arteries). Throughoutthe life of the patient, multiple factors contribute to the developmentof microscopic and/or macroscopic vascular lesions known as plaques.

The development of a plaque-lined vessel typically leads to an irregularinner vascular surface with a corresponding reduction of lumencross-sectional area. The progressive reduction in cross-sectional areacompromises flow through the vessel. In the case of the coronaryarteries, the result is a reduction in blood flow to the cardiac muscle.This reduction in blood flow, coupled with a corresponding reduction innutrient and oxygen supply, often results in clinical angina, unstableangina, myocardial infarction (heart attack), and death. The clinicalconsequences of the above process and its overall importance areevidenced by the fact that atherosclerotic coronary artery diseaserepresents the leading cause of death in the United States today.

Historically, for coronary artery disease states beyond those which canbe treated solely with medication, the treatment of advancedatherosclerotic coronary artery disease involved cardio-thoracic surgeryin the form of coronary artery bypass grafting (CABG). In thatprocedure, the patient is placed on cardio-pulmonary bypass and theheart muscle is temporarily stopped. Repairs are then surgicallyaffected on the heart in the form of detour conduit grafted vessels toprovide blood flow around obstructions. While CABG has proven to bequite effective, it carries with it inherent surgical risks and requiresa lengthy, often painful recuperation period. In the United States aloneapproximately 150,000-200,000 people are subjected to open heart surgeryannually.

In 1977 a major advance in the treatment of atherosclerotic coronaryartery disease occurred with the introduction of a technique known asPercutaneous Transluminal Coronary Angioplasty (PTCA). PTCA involves theretrograde introduction, typically from an artery in the arm or leg tothe area of vessel occlusion, of a catheter with a small dilatingballoon at its tip. The catheter is guided through the arteries viadirect fluoroscopic guidance and passed across the luminal narrowing ofthe vessel. Once in place, the catheter balloon is inflated to severalatmospheres of pressure. This results in "cracking", "plastic" or othermechanical deformation of the lesion or vessel with a subsequentincrease in the cross-sectional area through the lesion. This in turnreduces obstruction and trans-lesional pressure gradients and increasesblood flow.

PTCA is an extremely effective treatment with a relatively lowmorbidity. The procedure has rapidly become the primary therapy in thetreatment of advanced atherosclerotic coronary disease throughout theUnited States and the world. By way of example, since its introductionin 1977, the number of PTCA cases now exceeds 300,000 per annum in theUnited States and in 1987, for the first time surpassed the number ofbypass operations performed. Moreover, as a result of PTCA, emergencycoronary artery bypass surgery is required in less than four percent ofpatients.

Typically, atherosclerosis is a diffuse arterial disease processexhibiting simultaneous patchy involvement in several coronary arteries.Patients with this type of widespread coronary involvement, whilepreviously not considered candidates for angioplasty, are now beingtreated due to technical advances and increased clinical experience.

Despite the major therapeutic advance in the treatment of coronaryartery disease which PTCA represents, its success has been hampered bythe development of vessel renarrowing or reclosure following dilation.During a period of hours or days post procedure, significant totalvessel reclosure may develop in up to 10% of cases. This occurrence isreferred to as "abrupt reclosure". However, the more common and majorlimitation of PTCA, is the development of progressive reversion of thevessel to its closed condition, negating any gains achieved from theprocedure.

This more gradual renarrowing process is referred to as "restenosis".Post-PTCA follow-up studies report a 10-50% incidence (averagingapproximately 30%) of restenosis in cases of initially successfulangioplasty. Studies of the time course of restenosis have shown that itis typically an early phenomenon, occurring almost exclusively withinthe six months following an angioplasty procedure. Beyond this six-monthperiod, the incidence of restenosis is quite rare. Despite recentpharmacologic and procedural advances, little success has been achievedin preventing either abrupt reclosure or restenosis post-angioplasty.

Restenosis has become even more significant with the increasing use ofmulti-vessel PTCA to treat complex coronary artery disease. Studies ofrestenosis in cases of multi-vessel PTCA reveal that after multi-lesiondilatation, the risk of developing at least one recurrent coronarylesion ranges from about 26% to 54% and appears to be greater than thatreported for single vessel PTCA. Moreover, the incidence of restenosisincreases in parallel with the severity of the pre-angioplasty vesselnarrowing. This is significant in light of the growing use of PTCA totreat increasingly complex multi-vessel coronary artery disease.

The 30% overall average restenosis rate has significant costs includingpatient morbidity and risks as well as medical economic costs in termsof follow-up medical care, repeat hospitalization and recurrentcatherization and angioplasty procedures. Most significantly, prior torecent developments, recurrent restenosis following multiple repeatangioplasty attempts could only be rectified through cardiac surgerywith the inherent risks noted above.

In 1987, a mechanical approach to human coronary artery restenosis wasintroduced. That approach is commonly referred to as "IntracoronaryStenting". One type of intracoronary stent is a tubular device made offine wire mesh, typically stainless steel. A stent of that type isdisclosed in U.S. Pat. No. 4,655,771. The device can be radiallycompressed so as to be of low cross-sectional area. In this "lowprofile" condition, the mesh is placed in or on a catheter similar tothose used for PTCA. The stent is then positioned at the site of thevascular region to be treated. Once in position, the wire mesh stent isreleased and allowed to expand to its desired cross-sectional areagenerally corresponding to the internal diameter of the vessel. Similarsolid stents are also disclosed in U.S. Pat. No. 3,868,956 to Alfidi etal.

The metal stent functions as a permanent intra-vascular scaffold. Byvirtue of its material properties, the metal stent provides structuralstability and direct mechanical support to the vascular wall. Stents ofthe type described above are resiliently self-expanding due to theirhelical "spring" geometry. Recently, slotted steel tubes and extendedspring designs have been introduced. These are deployed throughapplication of direct radial mechanical pressure conveyed by a balloonor other radial expansion device at the catheter tip. Such a device andprocedure are disclosed in U.S. Pat. No. 4,733,665 to Palmaz. Despitecertain significant limitations and potentially serious complications(discussed below), this type of stent has been successful with an almost100% acute patency rate and a marked reduction in the restenosis rate.

Other stents have also been designed in recent years. Among these arestents formed from polymeric materials and stents formed from materialswhich exhibit shape memory. In the latter case, stents formed from theshape memory alloy Nitinol have been disclosed in the prior art.

The complications associated with permanent implants such as the Palmazdevice result from both the choice of material, as well as the inherentdesign deficiencies in the stenting devices. The major limitation liesin the permanent placement of a non-retrivable, non-degradable, foreignbody in a vessel to combat restenosis which is predominately limited tothe six-month time period post-angioplasty. There are inherent,significant risks common to all permanent implant devices. Moreover,recent studies have revealed that atrophy of the media, the middlearterial layer of a vessel, may occur as a specific complicationassociated with metal or other permanent stenting due to the applicationof continuous lateral expansile forces after implantation.

These problems are even more acute in the placement of a permanentmetallic foreign body in the vasculature associated with the cardiacmuscle. Coronary arteries are subjected to extreme service demandsrequiring continuous unobstructed patency with unimpeded flow throughoutthe life of the patient. Failure in this system can lead to myocardialinfarction (heart attack) and death. In addition, torsional and othermulti-directional stresses encountered in and near the heart, due to itscontinuous oscillatory/cyclic motion, further amplify the risksassociated with permanent, stiff intra-arterial implants in the coronaryregion.

It has been observed that, on occasion, recurrent intravascularnarrowing has occurred following stent placement in vessels during aperiod of several weeks to months. Typically, this occurs "peri-stent",i.e., immediately upstream or downstream from the stent. It has beensuggested that this may relate to the often significantly differentcompliances of the vessel and the stent, sometimes referred to as"compliance mismatch". Aside from changes in compliance, anotherimportant mechanism leading to luminal narrowing above and below thestent may be the changes in shear forces and fluid flows encounteredacross the sharp transitions of the stent-vessel interface. Furthersupporting evidence has resulted from studies of vascular grafts whichreveal a higher incidence of thrombosis and eventual luminal closurealso associated with significant compliance mismatch.

To date, known stent designs, (i.e., tubular, wire helical or spring,and scaffold) have been designed with little consideration ormeasurement of their radial stiffness. Recent studies measuring therelative radial compressive stiffness of known wire stents, as comparedto physiologically pressurized arteries, have found the stents to bemuch stiffer than biological tissue. These studies lend support to theconcept of poor mechanical biocompatibility of currently availablestents.

Conventional metal stenting is also limited since it requires theavailability of numerous stents of differing sizes (as well asassociated deployment devices) to accommodate treatment of blood vesselsof differing sizes. Additionally metal stents provide a relatively rigidnonflexible structural support which is not amenable to a wide varietyof endoluminal geometries, complex surfaces, luminal bends, curves orbifurcations.

The identified risks and limitations of metal and non-metal permanentstents have severely limited their utility in coronary arteryapplications. Thus, a need exists for stents which are non-permanent andhave a compliance that more closely matches that of blood vessels. Aneed also exists for stents which may be tailored in length and radialdiameter to properly match a wide variety of treatment sites. A needalso exists for methods for providing polymeric materials to variousbody lumens and hollow spaces, whether occurring naturally or as aresult of surgery, trauma or disease.

SUMMARY OF THE INVENTION

The present invention provides an alternative to conventional stentingtechniques as well as a method for providing biocompatible polymericmaterials in vivo. The invention relates to a novel method for polymericendoluminal paving and sealing (PEPS) which involves application of apolymeric material to the interior surface of a blood vessel, tissuelumen or other hollow space. The material may also be applied to tissuecontacting surfaces of implantable medical devices. In accordance withthis method, a polymeric material, either in the form of a monomer orprepolymer solution or in the form of an at least partially pre-formedpolymeric product, is introduced into the lumen or hollow space andpositioned at an area to be treated. The polymeric product is thenreconfigured to conform to and maintain intimate contact with theinterior surface of the lumen or hollow such that a paving and sealingcoating is achieved.

In general, the present invention relates to a method for forming abiocompatible polymer coating on a tissue surface by providing abiocompatible polymeric material that is non-fluent at body temperature,yet which becomes fluent at an elevated temperature. The material isheated to render it fluent, contacted with a tissue surface to becoated, and allowed to cool, thereby providing a non-fluentbiocompatible polymeric coating on the tissue surface. In connectionwith the step of contacting the polymeric material with the tissuesurface, the fluent polymeric material may be molded to provide acoating having desired surface or shape characteristics. The transitionof the polymer from a non-fluent state to a fluent state and vice versamay be the result of a phase change in which the polymeric material goesfrom a solid to a liquid state, or in the alternative, it may be theresult of a viscosity change with the polymeric material remaining in asingle phase throughout.

Although having particular advantages for preventing restenosis incoronary blood vessels following angioplasty, the PEPS approach is notlimited to use in connection with restenosis. The procedure can also beeffectively employed in any tubular or hollow organ to provide localstructural support, smooth surface characteristics, improved flow,barrier placement or imposition, and sealing of lesions. In addition,the polymeric paving and sealing material may incorporate therapeuticagents such as drugs, drug producing cells, cell inhibition and/orregeneration factors or even progenitor cells of the same type as theinvolved organ or a histologically different organ to accelerate and/orinhibit or retard healing processes. Materials with incorporatedtherapeutic agents may be effectively used to coat or plug hollow spacesor lumens formed by surgery, trauma or disease in normally solid organsas well as to coat or plug hollow spaces or lumens formed by surgery,percutaneous techniques, trauma or disease in normally hollow or tubularorgans.

The present invention also relates to the use of at least partiallypreformed polymeric products. These products may have any of a varietyof physical shapes and sizes in accordance with the particularapplication. The invention also provides apparatus specially adapted forthe positioning of the polymeric material, these including partiallypre-formed polymeric products, at the interior surface of an organ andfor the subsequent chemical or physical reconfiguration of the polymericmaterial such that it assumes a desired molded or customized finalconfiguration.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows an amorphous geometry of the PEPS polymer coating beforeand after deployment;

FIG. 2 shows a stellate geometry of the PEPS polymer coating before andafter deployment;

FIG. 3 shows a linear feathered polymer strip applied to "one" wallbefore and after deployment;

FIG. 4 shows a large patch of sprayed on polymer material before andafter deployment;

FIG. 5 shows a porous tubular form geometry before and after deployment;

FIG. 6 shows a spot geometry of the PEPS process before and afterdeployment;

FIG. 7 shows a spiral form application of the PEPS process before andafter deployment;

FIG. 8 shows an arcuate (radial, arc) patch geometry of the PEPS polymerbefore and after deployment;

FIG. 9 shows the deployed polymer paving layer in intimate contactapplied to a tissue surface;

FIG. 10a shows a pre-deployed polymer tube inside of an artery and apost-deployed, i.e., applied, polymer layer, subsequently applied to thesame vessel;

FIG. 10b shows the applied polymer paving layer under light microscopicmagnification applied to the endoluminal surface of the vessel;

FIGS. 11a and 11b show a human atherosclerotic cartoid artery with alumen obstructing plaque and the same vessel following paving with adilated polymer lined lumen;

FIG. 12a shows three examples of pre-deployed polymer tubes and theircorresponding post-deployed appearance;

FIG. 12b shows a pre-deployed tube in cross-section and a correspondingpost-deployment cross-section;

FIG. 13 shows an example of a typical polymer paving catheter with adistal occluding balloon, heating ports, a dilating thermoformingballoon and radiopaque markers. A pre-deployed polymer tube is in placeover the thermoforming balloon.

DETAILED DESCRIPTION OF THE INVENTION

In general, PEPS involves the introduction of a polymeric material ontoa selected location on a tissue surface or a tissue-contacting surfaceof an implantable medical device. The tissue surface may be an internalor external surface, and can include the interior of a tissue lumen orhollow space whether naturally occurring or occurring as a result ofsurgery, percutaneous techniques, trauma or disease. The polymericmaterial is then reconfigured to form a coating or "paving" layer inintimate and conforming contact with the interior surface. The resultingpaving layer optionally can have a sealing function. As used herein, theterm "sealing" or "seal" means a coating of sufficiently low porositythat the coating provides a barrier function. The term "paving" refersto coatings in general wherein the coatings are porous or perforated orare of a low porosity "sealing" variety. The coating preferably has athickness on the tissue surface on the order of 0.001-1.0 mm, however,coatings having a thickness outside that range may be used as well. Byappropriate selection of the polymeric material employed and of theconfiguration of the paving material, PEPS provides a uniquecustomizable process, which can be tailored to satisfy a wide variety ofbiological or clinical situations.

Broadly, the polymeric material comprises a biocompatible polymericmaterial having a variable degree of fluency in response to a stimulus.Thus, the material may be such that it is substantially non-fluent invivo. The material can be positioned adjacent to a tissue or non-tissuesurface to be coated and then stimulated to render it fluent. The fluentpolymeric material is contacted with the surface to be paved, and thepolymer is then allowed to return to its non-fluent state, therebyproviding a coating in the form of a biocompatible polymeric paving onthe surface.

Generally, the paving process is carried out by providing abiocompatible polymeric material that is non-fluent at body temperature,yet which may be rendered fluent at an elevated temperature. Thematerial is positioned at either an internal or external treatmentlocation and then heated to render the polymeric material fluent. Thefluent polymeric material is contacted with the tissue surface to bepaved or sealed, and the polymer is then allowed to cool into anon-fluent coating in the form of a biocompatible polymeric paving onthe tissue surface.

During the step of positioning the material at the desired location, thelocation may be accessed by either invasive surgical techniques or byrelatively non-invasive techniques such as laparoscopic procedures orpercutaneous transluminal procedures. In one embodiment, the step inwhich the fluent polymeric material is contacted with the tissue surfacemay be considered as a "molding" procedure in which the fluent polymericmaterial is molded into substantially conforming contact with the bodytissue before cooling into a non-fluent coating on the surface. It isnoted that the transition of the material from a non-fluent to a fluentstate, and vice-versa, may involve a phase change in the material,however, such a phase change is not necessary. For example, in certainembodiments, the terms "non-fluent" and "fluent" are primarily relativedescriptions of a material which undergoes a significant change inviscosity and flowability without undergoing an actual phase change.Alternatively, the transition of the material between its fluent andnon-fluent states may be the result of an actual phase change in thematerial resulting either from the addition or removal of energy fromthe material.

The basic requirements for the polymeric material to be used in the PEPSprocess are biocompatibility and the capacity to be chemically orphysically reconfigured under conditions which can be achieved in vivo.Such reconfiguration conditions may involve heating, cooling, mechanicaldeformation, (e.g., stretching), or chemical reactions such aspolymerization or crosslinking.

Suitable polymeric materials for use in the invention include bothbiodegradable and biostable polymers and copolymers of carboxylic acidssuch as glycolic acid and lactic acid, polyalkylsulfones, polycarbonatepolymers and copolymers, polyhydroxybutyrates, polyhydroxyvalerates andtheir copolymers, polyurethanes, polyesters such as poly(ethyleneterephthalate), polyamides such as nylons, polyacrylonitriles,polyphosphazenes, polylactones such as polycaprolactone, polyanhydridessuch as poly bis(p-carboxyphenoxy)propane anhydride! and other polymersor copolymers such as polyethylenes, hydrocarbon copolymers,polypropylenes, polyvinylchlorides and ethylene vinyl acetates.

The paving material is preferably a homopolymer, or a binary or teriarycopolymer, however, copolymers having more than three constituents areintended to be included as well.

The polymers and copolymers may sometimes contain additives such asplasticizers (e.g., citrate esters), to improve their function, such asto reduce the temperature at which sufficient fluency is obtained. Inaddition, physical blends of polymers including the combinations ofseveral different biostable and/or biodegradable polymers could beutilized in this process. Likewise the process allows polymericcomposites or blends of the polymers described above incorporatingseparate polymeric, metallic, or other, material domains to beintroduced onto tissue or tissue contacting surfaces. Such domains maybe present as randomly or uniformly distributed microparticles,microcapsules, nanoparticles, nanocapuless or liposomes of uniform orrandom size shape or compositions.

Other bioabsorbable polymers could also be used either singly or incombination. For example, homopolymers and copolymers ofdelta-valerolactone and p-dioxanone as well as their copolymers can becrosslinked with bis-caprolactone to provide material for use in PEPS.Likewise, copolymers of polycaprolactones and lactides are alsoconsidered to be particularly useful in the present invention.

In one embodiment, PEPS utilizes biodegradable polymers, with specificdegradation characteristics to provide material having a sufficientlifespan for the particular application. As used herein, "biodegradable"is intended to describe polymers and copolymers that are non-permanentand removed by natural or imposed therapeutic biological and/or chemicalprocesses. As such, bioerodable or bioabsorbable polymers and the likeare intended to be included within the scope of that term. As notedabove, a six month lifespan is probably sufficient for use in preventingrestenosis. Shorter or longer periods, or permanent biostable materialsmay be appropriate for other therapeutic applications.

The polycaprolactones disclosed in U.S. Pat. No. 4,702,917 to Schindler,incorporated herein by reference, are highly suitable bioabsorbablepolymers for use in the PEPS process, particularly for prevention ofrestenosis. Polycaprolactones possess adequate mechanical strength beingmostly crystalline even under quenching conditions. Despite theirstructural stability, polycaprolactones are much less rigid than themetals used in traditional stenting, thereby minimizing the risk ofacute vessel wall damage from sharp or rough edges. In the case of apolycaprolactone, for example, the crystalline structure of the polymerwill maintain a constant outside diameter. This eliminates risks oftenassociated with known helical or spring metal stents which, after beingexpanded in vivo, have a tendency to exert continuous pressure on thevessel wall.

The rate of bioabsorption of polycaprolactone is ideal for theapplications of the invention. The degradation process of this polymerhas been well characterized with the primary degradation product beingnontoxic 6-hydroxy hexanoic acid of low acidity. Furthermore, the timeover which biodegradation of polycaprolactone occurs can be adjustedthrough copolymerization.

Polycaprolactone has a crystalline melting point of 60° C. and can bedeployed in vivo via a myriad of techniques which facilitate transientheating and varying degrees of mechanical deformation or application asdictated by individual situations. This differs markedly from otherbioabsorbable polymers such as polyglycolide and polylactide which meltat much higher temperatures (approximately 180° C.) thereby raising thepossiblility of deleterious tissue exposure to due excessivetemperatures.

Polyanhydrides have been described for use as drug carrier matrices byLeong et al., J. Biomed. Mat. Res. 19,941-955 (1985). These materialsfrequently have fairly low glass transition temperatures, in some casesnear normal body temperature, which makes them mechanically deformablewith only a minimum of localized heating. Furthermore, they offererosion times varying from several months to several years depending onparticular polymer selected.

Heating of the polymeric material to render it fluent may be achievedusing a variety of methods. For example, the polymer may be heated usinga heated fluid such as hot water or saline, or it may be heated usingradiofrequency energy or resistance heating. Alternatively, the polymermay be heated using light such as light having a wavelength in theinfrared, visible, or ultraviolet spectrum. In still other embodiments,heating may be achieved using microwaves or radiation produced byfission or fusion processes.

The polymeric materials may be applied in custom designs, with varyingthicknesses, lengths, and three-dimensional geometries (e.g. spot,stellate, linear, cylindrical, arcuate, spiral) to achieve varyingfinished geometries as depicted in FIGS. 1-8. Further, PEPS may be usedto apply polymer to the inner surfaces of hollow, cavernous, or tubularbiological structures (whether natural or artificially formed) in eithersingle or multiple polymer layer configurations. PEPS may also be used,where appropriate, to occlude a tissue lumen completely.

Further to the above, the paving coating may be applied as a continuouslayer either with or without perforations. As noted earlier, in the casein which the paving coating is applied without perforations, it isreferred to as a "seal" to act as a barrier layer on the surface of thetissue. Such coatings may also be used to provide structural support tothe tissue, locally deliver therapeutic agents to the tissue surface, orachieve any of the other therapeutic effects, either alone or incombination, described herein. Although porous or perforated pavinglayers do not provide a barrier effect, each of the other aspects of thematerial described herein may be achieved. It is noted that as usedherein the term "continuous" refers to coatings interconnected as asingle unit as opposed to "discontinuous" layers which are formed of aplurality of isolated, discontinuous domains of the coating material.

The polymeric materials used in PEPS can be combined with a variety oftherapeutic agents for on-site delivery. Examples of such materials foruse in coronary artery applications are anti-thrombotic agents, e.g.,prostacyclin, heparin and salicylates, thrombolytic agents e.g.streptokinase, urokinase, tissue plasminogen activator (TPA) andanisoylated plasminogen-streptokinase activator complex (APSAC),vasodilating agents i.e. nitrates, calcium channel blocking drugs,anti-proliferative agents i.e. colchicine and alkylating agents,intercalating agents, antisense oligonucleotides, ribozymes, aptomers,growth modulating factors such as interleukins, transformation growthfactor β and congeners of platelet derived growth factor, monoclonalantibodies directed against growth factors, anti-inflammatory agents,both steriodal and non-steroidal, modified extracellular matrixcomponents or their receptors, lipid and cholesterol sequestrants andother agents which may modulate vessel tone, function, arteriosclerosis,and the healing response to vessel or organ injury post intervention. Inapplications where multiple polymer layers are used, differentpharmacological agents could be used in different polymer layers.Moreover, PEPS may be used to effect pharmaceutical delivery focallywithin the vessel wall, i.e. media. It is noted that delivery oftherapeutic agents is not limited to coronary artery applications.Rather, any tissue surface that may benefit from the local applicationof therapeutic agents is contemplated as a site for treatment using themethods and apparatus for the present invention.

The polymeric material in accordance with the invention may also haveincorporated in it living cells (whether naturally occurring or producedthrough recombinant DNA technology), artificial cells, cell ghosts(i.e., RBC or platelet ghosts), liposomes, or pseudoviriones, to serveany of several purposes. For example, the cells may be selected toproduce specific agents such as growth factors at the local tissuelocation. In such a way, a continuously regenerating supply of atherapeutic agent may be provided without concerns for stability,initial overdosing and the like.

Cells incorporated in the polymeric material may also be progenitorcells corresponding to the type of tissue at the treatment location orother cells providing therapeutic advantages. For example, liver cellsmight be incorporated into the polymeric material and implanted in alumen created in the liver of a patient to facilitate regeneration andclosure of that lumen. This might be an appropriate therapy in caseswhere disease (e.g. cirrhosis, fibrosis, cystic disease or malignancy)results in non-functional tissue, scar formation or tissue replacementwith cancerous cells. Similar methods may be applied to other organs aswell. The process of carrying out such treatment involves firstinserting a catheter into a lumen within a diseased organ segment. Thelumen can be a native vessel or it can be a man-made lumen, for example,a cavity produced by a laser. A polymeric plug is introduced into thelumen. The catheter is then removed, leaving the plug in place to act asa focus for new growth stemming from cells implanted along with thepolymeric plug. If the desire is for a more tubular structure, the plugcan be appropriately reconfigured.

Optional additions to the polymeric material such as barium, iodine ortantalum salts for X-ray radio-opacity allow visualization andmonitoring of the coating.

The technique of PEPS preferably involves the percutaneous applicationof a polymeric material, for example, a biodegradable polymer such aspolycaprolactone, either alone or mixed with other biodegradablepolymeric materials. As noted above, the polymeric material mayoptionally contain various pharmaceutical or therapeutic agents forcontrolled sustained release at the treatment location. The polymericmaterial is typically applied to an organ surface using both thermal andmechanical means to manipulate the polymeric material. Although capableof being used during conventional surgery, PEPS will generally beapplied using minimally invasive surgical techniques. The coatingtypically will be applied using some type of catheter, such as amodified PTCA catheter. PEPS is preferably applied using a singlecatheter with single or multiple balloons and lumens. The cathetershould be of relatively low cross-sectional area. A long thin tubularcatheter manipulated using fluoroscopic guidance is preferred forproviding access to the interior of organ or vascular areas.

The polymer may be deployed in the interior of the vessel or organ fromthe surface or tip of the catheter. Alternatively, the polymer could bepositioned on a balloon such as that of a standard angioplasty ballooncatheter. Additionally, the polymer could be applied by spraying,extruding or otherwise internally delivering the polymer via a longflexible tubular device having multiple lumens.

The polymeric material may take the form of a sleeve designed to bereadily insertable along with the catheter into the tissue lumen, andthen to be deployed onto the wall of the lumen to form the coating. Thisdeployment can be accomplished by positioning a polymeric preform overthe balloon portion of a dilatation catheter, and partially inflatingthe balloon to hold the preform in position. Upon guiding the preform toa desired treatment site, the preform is rendered fluent using, forexample, heated saline. The balloon is then fully inflated, whichexpands the fluent polymeric preform, causing it is press against thewalls of the tissue lumen and acquire a shape corresponding to the lumenwall. This shape is then fixed, upon cooling of the preform to anon-fluent state, and the catheter is removed leaving behind a polymericpaving or seal on the lumen wall.

The process of fixing the shape of the polymeric material can beaccomplished in several ways, depending on the character of the originalpolymeric material. For example, a partially polymerized material can beexpanded using the balloon after which the conditions are adjusted suchthat polymerization can be completed, e.g., by increasing the localtemperature or providing infrared, visible, or UV radiation through anoptical fiber. A temperature increase might also be used to soften afully polymerized sleeve to allow expansion and facilitatereconfiguration and local molding, after which it would "freeze" in theexpanded position when the heat source is removed. If the polymericsleeve is a plastic material which will permanently deform uponstretching (e.g., polyethylene, nylon or polyvinyl chloride), no specialfixation procedure is required.

Local heating can be provided by a flow of heated liquid directly intothe tissue lumen. Thermal control can also be provided, however, using afluid flow through or into the balloon, or using a partially perforatedballoon such that temperature control fluid passes through the ballooninto the lumen. Thermal control can also be provided using electricalresistance heating via a wire running along the length of the catheterbody in contact with resistive heating elements. This type of heatingelement can make use of DC or radio frequency (RF) current or externalRF or microwave radiation. Other methods of achieving temperaturecontrol can also be used, including light-induced heating using aninternal optical fiber (naked or lensed).

Variations in the ultimate configuration of the PEPS coating can also beachieved by using more complex deployments of the polymer on theexpansile number. For example, the polymer can be in the form of aperforated tubular sleeve, a helical sleeve or a plurality ofdiscontinuous members of various shapes. These may be affixed to theexpansile member directly, for example with an adhesive, or by suctionthrough perforations and the like, or the affixation can be achievedusing an overcoating such as dissolvable gauze-like or paper sheath(i.e. spun saccharide). Alternatively, the polymer can be held in placeby a retractable or porous sheath which will be removed with thecatheter after application.

Application of the polymeric material may be accomplished by extruding asolution of monomers or prepolymers through a catheter to coat or fill atissue lumen or hollow space. The formation of a polymer coating can becontrolled by introducing crosslinking agents or polymerizationcatalysts together with the monomer or prepolymer solution and thenaltering the conditions such that polymerization occurs. Thus, when aballoon catheter is used, a flow of heated fluid into the balloon canincrease the local temperature to a level sufficient to induce oraccelerate polymerization. Alternatively, the monomer/prepolymersolution might be introduced cold, with metabolic temperature beingsufficient to induce polymerization.

Catheter bodies for use in this invention can be made of any knownmaterial, including metals, e.g. steel, and thermoplastic polymers.Occluding balloons may be made from compliant materials such as latex orsilicone, or non-compliant materials such as polyethylene terephthalate(PET). The expansile member is preferably made from non-compliantmaterials such as PET, PVC, polyethylene or nylon. If used, the ballooncatheter portion of a dilatation may optionally be coated with materialssuch as silicones, polytetrafluoroethylene (PTFE), hydrophilic materialslike hydrated hydrogels and other lubricious materials to aid inseparation of the polymer coating.

In addition to arteries, the PEPS process may be utilized for otherapplications such as paving the interior of veins, ureters, urethras,bronchi, biliary and pancreatic duct systems, the gut, nasolacrimalducts, sinus cavities, the eye, and eustachian, spermatic and fallopiantubes. Likewise the process may be used to provide a paving layer in thecontext of transhepatic portosystemic shunting, dialysis grafts,arterio-venous fistulae, and aortic and other arterial aneurysms. Thepaving and sealing material of the PEPS process can also be used inother direct clinical applications even at the coronary level. Theseinclude but are not limited to the treatment of abrupt vessel reclosurepost PCTA, the "patching" of significant vessel dissection, the sealingof vessel wall "flaps" either secondary to catheter injury orspontaneously occurring, or the sealing of aneurysmal coronary dilationsassociated with various arteritidies. Further, PEPS providesintraoperative uses such as sealing of vessel anastomoses duringcoronary artery bypass grafting and the ability to provide a "bandaged"smooth polymer surface.

The unique pharmaceutical delivery function of the PEPS process may bereadily combined with "customizable" deployment geometry capabilities toaccommodate the interior of a myriad of complex organ or vesselsurfaces. Most importantly, this customized geometry can be made fromstructurally stable yet biodegradable polymers. The ability to tailorthe external shape of the deployed polymer through melted polymer flowinto uneven surface interstices, while maintaining a smooth interiorsurface with good flow characteristics, will facilitate betterstructural support for a variety of applications including eccentriccoronary lesions which by virtue of their geometry are not well bridgedwith conventional metal stents.

As noted above, a polymer substrate used in PEPS may be fashioned out ofextruded tubes of polycaprolactone or copolymers containingpolycaprolactone. The initial predeployment design and size of thepolymer sleeve will be dictated by the specific application based uponthe final deployed physical, physiological and pharmacologicalproperties desired. In an alternative embodiment, the polymeric materialmay be provided in the form of a rolled sheet of material which isradially expanded and pressed into contact with a tissue surface by anunrolling procedure. The material of the rolled sheet may be renderedfluent prior to, during, or following the unrolling procedure.

For coronary artery application, predeployment tubes of about 10 to 20mm in length and about 1 to 2 mm in diameter may be used. The initialwall thickness of the resulting in vivo polymer layer may be varieddepending upon the nature of the particular application. In general,coating procedures require polymer layers of about 0.001 to 1.0 mm whilelayers which are designed to give structural support can vary from 0.05mm to 5.0 mm.

The polymer tube walls may be processed prior to insertion with eitherlight-induced or chemical etching, pitting, slitting or perforationdepending upon the applications n addition, the shape of any micro (10nm to 1 μm ) or macro (>1 μm to 4.0 mm) perforation may be furthergeometrically modified to provide various surface areas on the innerversus outer seal surface. The surfaces of the predeployed polymer maybe further modified with bound, coated, or otherwise applied agents,i.e., cyanoacrylates or biological adhesives such as those derived fromfungal spores, sea mussel or autologous fibrinogen adhesive derived fromblood.

For PEPS applications involving the coronary arteries, the polymer tubes(if in an initial tubular configuration), may include perforations orpores. This will ensure a symmetric expansion of the encasing polymericsealant. By using a fragmented tubular polymer surface withcorresponding expansions along predicted perforations, a significantmechanical stability is provided. In addition, the amount of foreignmaterial placed within the vessel would be minimized.

Depending upon the polymer and pharmaceutical combination and theconfiguration, PEPS may be used to coat or bandage the inner surface ofan organ with a thin adhesive partitioning polymer film or layer ofabout 0.005 mm to 1.0 mm. Biodegradable polymers thus applied to aninternal organ or vessel surface will act as an adherent film "bandage".This improved surface, with desirable rheologic and adherenceproperties, facilitates improved fluid or gas transport in and throughthe body or lumen of the vessel or hollow organ structure and acts toreinstate violated native surfaces and boundaries.

The ultimate in vivo deployed geometry of the polymer dictates the finalfunction of the polymer coating. The thinner applications allow thepolymer film to function as a coating, sealant, partitioning barrier,bandage, and/or drug depot. Complex internal applications of thickerlayers of polymer, such as intravessel or intra-luminal applications canprovide increased structural support, and can serve a mechanical role tomaintain vessel or organ patency.

For example, lesions which are comprised mostly of fibromuscularcomponents have a high degree of visco-elastic recoil. These lesionswould require using the PEPS process to apply an intraluminal coating ofgreater thickness and extent so as to impart more structural stabilitythereby resisting vessel radial compressive forces. The PEPS process inthis way provides structural stability and is generally applicable forthe maintenance of the intraluminal geometry of tubular biologicalorgans or substructures. It may be used in this way following thetherapeutic return of normal architecture associated with balloondilation (PTCA), atherectomy, or any recanalization procedures, however,the use is not intended to be limited as such.

An important feature of the PEPS technique is the ability to customizethe application of the polymer to the internal surface of a vessel ororgan as dictated by the particular application. This results in avariety of possible geometries of polymer as well as a variety of forms.These multi-geometry, multi-form polymer structures may be adjusted tocorrespond to particular functions. (FIGS. 1-8)

With particular reference to FIGS. 1-8 the PEPS process may beeffectuated so that the focal application of polymer to the vessel ororgan results in either an amorphous geometry, FIG. 1, stellategeometry, FIG. 2, or spot geometry, FIG. 6.

Additional geometries could include a linear feathered polymer stripapplied to a particular area of the vessel wall as shown in FIG. 3. FIG.4 shows a large patch of polymer which can be sprayed on using a varietyof known techniques. Another form of the PEPS application to be utilizedin instances, e.g., where structural stability need be imparted to thevessel would be the porous tubular form shown in FIG. 5. Other types ofPEPS applications which would impart structural stability to the vesselwould be the spiral form application shown in FIG. 7, or the arcuate(radial, arc) patch as shown in FIG. 8.

Conversely, in cases where the severely denuded lesions have irregularsurfaces with less fibromuscular components the PEPS process can be usedto provide only a thin polymer film to act as a bandage.

The PEPS process is significantly different and is conceptually anadvance beyond stents and stenting in achieving vessel patency. Stentshave been designed with the underlying primary function of providing arelatively stiff structural support to resist post-PTCA vessel reclosurecaused by the vessel's spring-like characteristics. It has beenincreasingly demonstrated that cellular and biochemical mechanisms asopposed to physical "spring-like" coils, are of a much greatersignificance in preventing vessel reclosure and PEPS addresses thesemechanisms.

The specific object and features of the PEPS process are best understoodby way of illustration with reference to the following examples.

The invention may be readily understood through a description of anexperiment performed in vitro using a mock blood vessel made fromtransparent plastic tubing using a heat-balloon type deployment catheterreference to FIG. 13.

FIG. 13 shows a paving catheter having a tubular shaft 105 which, at itsdistal end, includes a distal tip 106, a distal occlusion balloon 108, apair of exit ports 110, radiopaque markers 112, a paving balloon 114,and a polymer tube 116 to be paved onto the interior of a tubular lumen.The distal occlusion balloon 108 is used to occlude the distal end of atreatment site during the paving process. The exit ports 110 are used toinject a heated saline solution into the treatment site to heat thepolymer material 116 and render it fluent for paving. The paving balloon114 is used to mold the fluent polymeric tube 116 into contact with thelumen surface, and the markers 112 are used to provide visualization ofthe distal end of the device using fluoroscopic methods. It is notedthat the catheter device of FIG. 13 is merely one of a wide variety ofdevices that may be used in the PEPS process, and that the procedure isnot intended to be limited strictly to the use of that device.

EXAMPLE 1

A polycaprolactone polymer tube was placed in a low profile conditionsurrounding a balloon at the distal end of a delivery catheter. Thedelivery catheter (FIG. 13) with the polycaprolactone tube was theninserted, occlusion balloon end first, into the vessel and manipulatedinto position at the area of the vessel to be treated.

The distal occlusion balloon on the end of the occlusion catheter wasinflated to create a stagnant column of "blood" in the vessel around theballoon delivery catheter and polycaprolactone tube. Saline solution atabout 60-80° C. was injected into the area surrounding the deliverycatheter, paving balloon and polycaprolactone tube. Once thepolycaprolactone tube became fluent, the delivery catheter balloon wasinflated to direct the flow of the fluent polycaprolactone and"thermoform" it against the interior wall.

The polycaprolactone conformed to the inner surface of the vessel,flowing into and filling in surface irregularities, thereby creating a"tailored" fit. As shown in FIG. 9 the tissue surface 100 having amicro-indentation 102 is paved with polycaprolactone 104 in a mannerwhich coats the surface and fills and conforms to the indention.Further, the deployed interior surface of the PEPS polymer was smoothproviding an increased vessel (lumen) cross-section diameter and arheologically advantageous surface with improved blood flow. Uponcessation of heating the polymer rapidly recrystallized providing apaved surface on the vessel wall interior.

The deployment catheter paving balloon was then deflated leaving thepolycaprolactone layer in place. The distal occlusion balloon was thendeflated and blood flow was allowed to return to normal. The deploymentcatheter then was removed leaving the recrystallized polycaprolactonelayer in place within the vessel.

When performed in a living organism, it is expected that over the courseof time, the polycaprolactone seal will become covered with aproteinaceous biologic thin film coat. Depending upon the exact sealchemical composition, the polymer will then biodegrade at apredetermined rate, and "dissolve" in to the bloodstream or be absorbedinto the vessel wall. While in intimate contact with the vessel wall,pharmacological agents if embedded or absorbed in the polycaprolactonewill have a "downstream" effect if released slowly into the bloodstreamor may have a local effect on the blood vessel wall, therebyfacilitating healing of the angioplasty site, controlling or reducingexuberant media smooth muscle cell proliferation, promoting effectivelesion endothelialization and reducing lesion thrombogenicity.

EXAMPLE 2

Polycaprolactone in an initial macroporous tubular configuration wasplaced in a low profile form in bovine coronary arteries and caninecarotid arteries. In the process of deployment the vessels werepurposely over extended and sealed through thermal and mechanicaldeformation of the polymer. In FIG. 10a the pre-deployed polymer tube50, placed within a baseline vessel 52 may be seen. Following paving,the polymer is locally reconfigured forming an intimate coating 54 whichlines the endoluminal surface of the vessel 56. FIG. 10b, a histologicsection of a paved artery shows the adherent paving polymer layer inintimate contact with the arterial intimal surface 60.

All polymer sealed vessels remained dilated with a thin layer ofmacroporous polymer providing a new barrier surface between the vessellumen and the vessel wall constituents. The unsealed portion of thevessels did not remain dilated.

EXAMPLE 3

Polycaprolactone paving materials, both in tube and rolled sheet formwere placed ex vivo within the lumen of disease compromisedatherosclerotic human carotid and coronary arteries. As shown in FIGS.11a and 11b, following paving the partially obstructed narrowed carotidartery, with an eccentric atheroma 64 (FIG. 11a) was successfully pavedwith an intimate polymeric liner layer 66 providing a smooth endoluminalsurface. The liner layer effectively partitioned the atheroma andsupported the diseased arterial wall 68 yielding a patent dilated arterywith a large lumen 70 (FIG. 11b).

EXAMPLE 4

This example demonstrates some of the variety of post-deploymentconfigurations that may be achieved depending upon the initialprocessing of the pre-deployed tube. In FIG. 12a, slits or perforationsyielding 10%, 30%, or 50% (72, 74, 76, respectively) open surface are aswere generated. Following paving in a normal vessel they yielded thecorresponding post-deployment polymer layers, i.e., 78, 80 and 82respectively. FIG. 12b shows an end on cross-sectional view of thepredeployed 84 and postdeployed 86 polymer, with wall thinning secondaryto local thermoforming being evident. Note a postdeployed tube such as82 forms an open scaffoled capable of acting as a support, whereas amore dense paving layer 78 yields a more continuous layer capable ofproviding increased surface contact as in the case in which it isdesired to fashion a local drug delivery depot.

These examples demonstrate that the PEPS process may, if desired,provide polymer application with a relatively large degree of surfacearea coverage and an effective polymer barrier shield. As such, thepolymer barrier shield may, if desired, impart sufficient structuralstability to maintain a selected vessel diameter. The selected finalvessel diameter at which a vessel is sealed is dictated by theparticular physicological variables and therapeutic goals which confrontthe PEPS user.

The geometry of the pre- and post-PEPS application sites may be readilyvaried. PEPS may be used to merely coat an existing vessel or organgeometry. Alternatively, the PEPS process may be used to impartstructural stability to a vessel or organ the geometry of which has beenaltered prior to the PEPS application. In addition, the PEPS process mayitself alter the geometry of the vessel or organ. With reference to FIG.10a this latter process was used to expand the vessel 52.

A specific and important attribute of the PEPS technique and thepolymers which are employed is the significantly lower degree ofcompliance mismatch or similarities of stiffness (inverse of compliance)between the vessel and the polymer seal as compared to metal stents. Thevessel damage from compliance mismatch discussed above may be eliminatedby the PEPS process utilizing a variety of available polymers.Additionally, compliance mismatch greatly modifies the characteristicsof fluid wave transmission along the vessel with resultant change inlocal flow properties, development of regional change in shear forcesand a subsequent vessel wall hypertrophy which acts to reduce vesselcross-sectional area and reduces blood flow. Further, the substructuralreduction of compliance mismatch of the PEPS technique at firstminimizes and then, upon dissolution eliminates local flow abnormalitiesand up and downstream transition zone hypertrophy associated with metalstenting.

PEPS has the flexibility of being safely and effectively usedprophylactically at the time of initial PTCA in selected patients orbeing incorporated as part of the original dilation procedure as asecond stage prophylactic vessel surface "finishing" process. Forexample, the invasive cardiologist may apply the PEPS technique on awide clinical basis after the first episodes of restenosis. In addition,because the PEPS technique significantly aids in the vascular healingprocess post intervention, it may be readily used prophylactically afterinitial angioplasty prior to any incidence of restenosis. This wouldfree the patient from the risks of repeat intracoronary procedure aswell as those associated with metal stenting.

EQUIVALENTS

Although specific features of the invention are shown in some drawingsand not in others, it is for convenience only as each feature may becombined with any or all of the other features in accordance with theinvention. It should be understood, however, that the foregoingdescription of the invention is intended merely to be illustrativethereof by way of example, and that other modifications, embodiments,and equivalents may be apparent to those skilled in the art withoutdeparting from its spirit. It will be understood by those of ordinaryskill in the art that variations such as the use of polymers other thanthose described can be substituted or added consistent with thisinvention.

Having thus described the invention, what we desire to claim and secureby Letters Patent is:
 1. An in vivo method for forming a biocompatiblepolymeric coating on tissue or tissue-contacting surfaces whichcomprises the steps of:a) providing a biocompatible polymeric materialwhich is non-fluent at body temperature and which is fluent at anelevated temperature; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) heating the polymeric material to render thepolymeric material fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to cool into a non-fluent biocompatible coating onthe surface,wherein the polymeric coating is biodegradable.
 2. A methodas in claim 1 wherein the biodegradable polymeric coating furtherincludes a therapeutic agent.
 3. A method as in claim 2 wherein thetherapeutic agent is selected from the group consisting ofanti-thrombotic agents, thrombolytic agents, vasodilating agents,anti-proliferative agents, intercalating agents, growth modulatingfactors, monoclonal antibodies, anti-imflammatory agents, lipid andcholesterol sequestrants, antisense oligonucleotides, ribozymes,aptomers, and combinations thereof.
 4. An in vivo method for forming abiocompatible polymeric coating on tissue or tissue-contacting surfaceswhich comprises the steps of:a) providing a biocompatible polymericmaterial which is non-fluent at body temperature, the fluency of whichcan be changed by a change in temperature of the material; b)positioning the polymeric material at a position substantially adjacentto the tissue or tissue-contacting surface to be coated; c) modifyingthe temperature of the polymer to render it fluent; d) molding thefluent polymeric material into substantially conforming contact with thesurface; and e) allowing the polymeric material to reach bodytemperature, thereby forming a non-fluent biocompatible coating on thesurface, wherein the tissue surface comprises a lumen in a body vessel.5. A method as in claim 4 wherein the body vessel comprises a bloodvessel.
 6. A method as in claim 5 wherein the polymeric cylinder ispositioned using a dilatation catheter having a radially expandableportion.
 7. A method as in claim 6 wherein prior to the molding step,the polymeric cylinder is positioned about the radially expandableportion of the dilatation catheter.
 8. A method as in claim 7 whereinthe molding is achieved by expanding the radially expandable portion ofthe dilatation catheter.
 9. A method as in claim 4 wherein prior to themolding step, the biocompatible polymeric material comprises a polymericcylinder having an outside diameter that is substantially smaller thanthe diameter of the tissue lumen.
 10. An in vivo method for forming abiocompatible polymeric coating on tissue or tissue-contacting surfaceswhich comprises the steps of:a) providing a biocompatible polymericmaterial which is non-fluent at body temperature, the fluency of whichcan be changed by a change in temperature of the material; b)positioning the polymeric material at a position substantially adjacentto the tissue or tissue-contacting surface to be coated; c) modifyingthe temperature of the polymer to render it fluent; d) molding thefluent polymeric material into substantially conforming contact with thesurface; and e) allowing the polymeric material to reach bodytemperature, thereby forming a non-fluent biocompatible coating on thesurface, wherein the modifying step comprises heating the polymer usingradio frequency energy, or radiation produced by fission or fusionprocesses.
 11. A method as in claim 10 wherein the temperature of thepolymer is modified using radio frequency energy.
 12. An in vivo methodfor forming a biocompatible polymeric coating on tissue ortissue-contacting surfaces which comprises the steps of:a) providing abiocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the modifyingstep comprises heating the polymer using light.
 13. A method as in claim12 wherein the light has a wavelength in the infrared, visible orultraviolet spectrum.
 14. An in vivo method for forming a biocompatiblepolymeric coating on tissue or tissue-contacting surfaces whichcomprises the steps of:a) providing a biocompatible polymeric materialwhich is non-fluent at body temperature, the fluency of which can bechanged by a change in temperature of the material; b) positioning thepolymeric material at a position substantially adjacent to the tissue ortissue-contacting surface to be coated; c) modifying the temperature ofthe polymer to render it fluent; d) molding the fluent polymericmaterial into substantially conforming contact with the surface; and e)allowing the polymeric material to reach body temperature, therebyforming a non-fluent biocompatible coating on the surface, wherein themodifying step comprises heating the polymer using resistance heating.15. An in vivo method for forming a biocompatible polymeric coating ontissue or tissue-contacting surfaces which comprises the steps of:a)providing a biocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the coatingcomprises a plurality of isolated domains.
 16. An in vivo method forforming a biocompatible polymeric coating on tissue or tissue-contactingsurfaces which comprises the steps of:a) providing a biocompatiblepolymeric material which is non-fluent at body temperature, the fluencyof which can be changed by a change in temperature of the material; b)positioning the polymeric material at a position substantially adjacentto the tissue or tissue-contacting surface to be coated; c) modifyingthe temperature of the polymer subsequent to or simultaneously with thepositioning step to render it fluent; d) molding the fluent polymericmaterial into substantially conforming contact with the surface; and e)allowing the polymeric material to reach body temperature, therebyforming a non-fluent biocompatible coating on the surface.
 17. A methodas in claim 16, wherein the providing step comprises providing abiocompatible polymeric material which is non-fluent at body temperatureand which is fluent at an elevated temperature, the modifying stepcomprises heating the polymeric material to render the polymericmaterial fluent, and the allowing step comprises allowing the polymericmaterial to cool into a non-fluent biocompatible coating on the surface.18. A method as in claim 17 wherein the biocompatible polymeric coatingis selected from the group consisting of polymers and copolymers ofcarboxylic acids, polyurethanes, polyesters, polyamides,polyacrylonitriles, polyphosphazenes, polylactones, polyanhydrides,polyethylenes, polyalkylsulfones, polycarbonates, polyhydroxybutyrates,polyhydroxyvalerates, hydrocarbon polymers, polypropylenespolyvinylchlorides, ethylene vinyl acetates, and combinations thereof.19. A method as in claim 16 wherein the biocompatible polymeric coatingis selected from the group consisting of polymers and copolymers ofcarboxylic acids, polyurethanes, polyesters, polyamides,polyacrylonitriles, polyphosphazenes, polylactones, polyanhydrides,polyethylenes, polyalkylsulfones, polycarbonates, polyhydroxybutyrates,polyhydroxyvalerates, hydrocarbon polymers, polypropylenespolyvinylchlorides, ethylene vinyl acetates, and combinations thereof.20. A method as in any of claims 18 or 19 wherein the polymer comprisesa material selected from the group of polycaprolactone,delta-valerolactone, p-dioxanone, polyglycolic acids, polylactic acids,and copolymers thereof.
 21. A method as in claim 17 wherein theresulting polymeric coating has a thickness in the range ofapproximately 0.001-1.0 mm.
 22. A method as in claim 17 wherein thepolymer is heated via a heated fluid.
 23. A method as in claim 22wherein the fluid is selected from the group consisting of water andsaline.
 24. A method as in claim 17 wherein the coating is a continuouslayer.
 25. A method as in claim 24 wherein the substantially continuouslayer includes perforations.
 26. A method as in claim 17 wherein thecoating opposite the tissue surface is substantially smooth.
 27. Amethod as in any of claims 17, or 16 wherein the biocompatible polymericmaterial comprises a physical blend of polymers selected from the groupconsisting of biostable polymers, biodegradable polymers, andcombinations thereof.
 28. A method as in any of claims 17, or 16 whereinmultiple coating layers are deposited to provide a composite coating.29. A method as in any of claims 18 or 19 wherein the polyamidecomprises nylon.
 30. A method as in claim 16 wherein the resultingpolymeric coating has a thickness in the range of approximately0.001-1.0 mm.
 31. A method as in claim 16 wherein the temperature of thepolymer is modified using a fluid.
 32. A method as in claim 31 whereinthe fluid is selected from the group consisting of water and saline. 33.A method as in claim 16 wherein the coating is a substantiallycontinuous layer.
 34. A method as in claim 33 wherein the substantiallycontinuous layer includes perforations.
 35. A method as in claim 16wherein the coating has a surface opposite the tissue surface that issubstantially smooth.
 36. A method as in claim 16 wherein the modifyingstep is carried out subsequent to the positioning step.
 37. A method asin claim 16 wherein the modifying step comprises modifying thetemperature of the polymer to effect a phase change in the material. 38.An in vivo method for forming a biocompatible polymeric coating ontissue or tissue-contacting surfaces which comprises the steps of:a)providing a biocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the polymericcoating is biodegradable.
 39. A method as in claim 12 wherein thebiodegradable polymeric coating further includes a therapeutic agent.40. A method as in claim 39 wherein the therapeutic agent is selectedfrom the group consisting of anti-thrombotic agents, thrombolyticagents, vasodilating agents, anti-proliferative agents, intercalatingagents, growth modulating factors, monoclonal antibodies,anti-inflammatory agents, lipid and cholesterol sequestrants, antisenseolgonucleotides, ribozymes, aptomers, and combinations thereof.
 41. Anin vivo method for forming a biocompatible polymeric coating on tissueor tissue-contacting surfaces which comprises the steps of:a) providinga biocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be chanced by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the tissuesurface comprises a lumen in a body vessel.
 42. A method as in claim 41wherein the body vessel comprises a blood vessel.
 43. A method as inclaim 42 wherein prior to the molding step, the biocompatible polymericmaterial comprises a polymeric cylinder having an outside diameter thatis substantially smaller than the diameter of the tissue lumen.
 44. Amethod as in claim 43 wherein the polymeric cylinder is positioned usinga dilatation catheter having a radially expandable portion.
 45. A methodas in claim 44 wherein prior to the molding step, the polymeric cylinderis positioned about the radially expandable portion of the dilatationcatheter.
 46. A method as in claim 45 wherein the molding is achieved byexpanding the radially expandable portion of the dilatation catheter.47. An in vivo method for forming a biocompatible polymeric coating ontissue or tissue-contacting surfaces which comprises the steps of:a)providing a biocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the modifyingstep comprises modifying the temperature of the polymer using light. 48.A method as in claim 47 wherein the light has a wavelength in theinfrared, visible or ultraviolet spectrum.
 49. An in vivo method forforming a biocompatible polymeric coating on tissue or tissue-contactingsurfaces which comprises the steps of:a) providing a biocompatiblepolymeric material which is non-fluent at body temperature, the fluencyof which can be changed by a change in temperature of the material; b)positioning the polymeric material at a position substantially adjacentto the tissue or tissue-contacting surface to be coated; c) modifyingthe temperature of the polymer to render it fluent; d) molding thefluent polymeric material into substantially conforming contact with thesurface; and e) allowing the polymeric material to reach bodytemperature, thereby forming a non-fluent biocompatible coating on thesurface, wherein the coating comprises a plurality of isolated domains.50. An in vivo method for forming a biocompatible polymeric coating ontissue or tissue-contacting surfaces which comprises the steps of:a)providing a biocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the polymercomprises poly(bis(p-carboxyphenoxy)propane anhydride).
 51. An in vivomethod for forming a biocompatible polymeric coating on tissue ortissue-contacting surfaces which comprises the steps of:a) providing abiocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein thebiocompatible polymeric material is coated on a tissue surface selectedfrom the group consisting of veins, arteries, urethras, bronchi, biliaryducts, pancreatic ducts, the gut, the eye, eustachian tubes, spermatictubes, fallopian tubes, arterio-venous fistulae, or aortic and otherarterial aneurysms.
 52. An in vivo method for forming a biocompatiblepolymeric coating on tissue or tissue-contacting surfaces whichcomprises the steps of:a) providing a biocompatible polymeric materialwhich is non-fluent at body temperature, the fluency of which can bechanged by a change in temperature of the material; b) positioning thepolymeric material at a position substantially adjacent to the tissue ortissue-contacting surface to be coated; c) modifying the temperature ofthe polymer to render it fluent; d) molding the fluent polymericmaterial into substantially conforming contact with the surface; and e)allowing the polymeric material to reach body temperature, therebyforming a non-fluent biocompatible coating on the surface, wherein thetissue contacting surface is selected from the group consisting ortranshepatic portosystemic shunts and dialysis grafts.
 53. An in vivomethod for forming a biocompatible polymeric coating on tissue ortissue-contacting surfaces which comprises the steps of:a) providing abiocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the coatingincorporates separate domains of material selected from the groupconsisting of polymeric and metallic material.
 54. An in vivo method forforming a biocompatible polymeric coating on tissue or tissue-contactingsurfaces which comprises the steps of:a) providing a biocompatiblepolymeric material which is non-fluent at body temperature, the fluencyof which can be changed by a chance in temperature of the material; b)positioning the polymeric material at a position substantially adjacentto the tissue or tissue-contacting surface to be coated; c) modifyingthe temperature of the polymer to render it fluent; d) molding thefluent polymeric material into substantially conforming contact with thesurface; and e) allowing the polymeric material to reach bodytemperature, thereby forming a non-fluent biocompatible coating on thesurface, wherein the coating incorporates elements selected from thegroup consisting of microparticles, nanoparticles, microcapsules,nanocapsules, liposomes, and combinations thereof.
 55. An in vivo methodfor forming a biocompatible polymeric coating on tissue ortissue-contacting surfaces which comprises the steps of:a) providing abiocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the polymer isbiodegradable and is crosslinked with a bis-caprolactone.
 56. An in vivomethod for forming a biocompatible polymeric coating on tissue ortissue-contacting surfaces which comprises the steps of:a) providing abiocompatible polymeric material which is non-fluent at bodytemperature, the fluency of which can be changed by a change intemperature of the material; b) positioning the polymeric material at aposition substantially adjacent to the tissue or tissue-contactingsurface to be coated; c) modifying the temperature of the polymer torender it fluent; d) molding the fluent polymeric material intosubstantially conforming contact with the surface; and e) allowing thepolymeric material to reach body temperature, thereby forming anon-fluent biocompatible coating on the surface, wherein the polymericmaterial is provided in the form of a rolled sheet which may be expandedinto contact with the surface to be coated.
 57. A method as in claim 56wherein the rolled sheet is rendered fluent prior to expansion.
 58. Amethod as in claim 56 wherein the rolled sheet is rendered fluentfollowing expansion.